1. Field of the Invention
The present invention is directed toward new isoxazolinones, methods for their use, and processes for their production. These novel isoxazolinone derivatives are useful as antimicrobial agents which are effective against a number of human and veterinary pathogens, including gram positive bacteria such as multiply-resistant staphylococci, streptococci, and enterococci (e.g. methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium).
2. Background
The literature contains a limited number of isoxazolinones used as pre-emergence herbicides. For example in U.S. Pat. No. 4,065,463, 2-methyl-4-(trifluoromethyl-m-tolyl)-3-isoxazolin-5-one and 2-methyl-4-(chloro-m-tolyl)-3-isoxazolin-5-one are disclosed as being useful in preventing the growth of weeds which have a deleterious effect on crop production. 
U.S. Pat. No. 4,000,155 discloses the related compound 1,2-dimethyl-4-(trifluoromethyl-m-tolyl)-3-pyrazolin-5-one for the same utility. 
The applicants are not aware of any literature which discloses the use of these compounds as broad spectrum anti-bacterial agents. A different ring system is disclosed in WO 98/07708, which discusses the use of isoxazoline derivatives as anti-bacterial agents, 
where W is a substituted aryl or heteroaryl system and V is H, or C1-C4 alkyl optionally substituted with F, Cl, OH, C1-C4 alkoxy, or acyloxy.
Oxazolidinones II shown below are a well known class of orally active antibacterial agents. The prior art contains numerous references to these compounds where Y and Z can include a wide variety of substituents. Specific substituted oxazolidinones are discussed in U.S. Pat. Nos. 4,705,799 and 5,523,403 (substituted phenyl 2-oxazolidinones), U.S. Pat. Nos. 4,948,801; 5,254,577; and 5,130,316 (arylbenzene oxazolidinyl compounds), U.S. Pat. No. 6,069,145 (piperazinophenyloxazolidinones) and European Patent Applications 0,697,412; 0,694,544; 0694,543; and 0,693,491 (5 to 9-membered heteroaryl substituted oxazolidinones). 
Additionally, certain compounds containing a substituted furanone ring have been reported to possess antibiotic activity. WO 97/14690 discloses 
where T is hydroxy or NHC(O)C1-C4 alkyl, M and L are each independently hydrogen or fluoro, G and H are are each independently hydrogen or methyl, K-L is of the formula Cxe2x95x90CH, CHCH2 or C(OH)CH2, I is O, SO, SO2 or a substituted nitrogen, and Q-R is CH2xe2x80x94CH2 or CHxe2x95x90CH2. Other substituted furanones are discussed in U.S. Pat. No. 5,708,169, WO 97/43280 and WO 97/10235.
Isoxazolinones of type III have been disclosed in PCT Publication WO 00/10566, but the compounds of the present invention are not disclosed or suggested in this publication. 
A first embodiment of a first aspect of the present invention is a compound of formula I 
or a pharmaceutically acceptable salt thereof, wherein:
L is oxygen or sulfur;
L1 is selected from the group consisting of: R4xe2x80x94(CH2)mxe2x80x94CR5(NR6R7)C(O)xe2x80x94, R8R9Nxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, C1-6alkylC(O)CH2C(O)xe2x80x94, R10xe2x80x94Xxe2x80x94CH2C(O)xe2x80x94, R10xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94, R10xe2x80x94NHC(O)CH2xe2x80x94, R10xe2x80x94(CH2)pxe2x80x94 and R10xe2x80x94S(O)2xe2x80x94;
m is 0 or an integer from 1 to 4;
n is an integer from 1 to 4;
p is an integer from 2 to 6;
X is selected from the group consisting of: a bond, sulfur, oxygen, NH and N(C1-4alkyl);
R1 is selected from the group consisting of: hydrogen, C1-8alkyl, C3-6cycloalkyl and C1-8alkoxy, said C1-8alkyl optionally substituted with one or more fluoro, chloro, hydroxy, C1-8alkoxy or C1-8acyloxy;
R2 and R3 are each independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, amino, cyano, C1-6alkyl, C1-6alkoxy and trifluoromethyl;
R4 is selected from the group consisting of: hydrogen, hydroxy, C1-6thioalkoxy, imidazolyl, indolyl, xe2x80x94CO2H and xe2x80x94NHC(xe2x95x90NH)NH2;
R5 is hydrogen or C1-6alkyl; or R4 and R5 taken together can be xe2x80x94CH2xe2x80x94 when m is 1;
R6 and R7 are each independently selected from hydrogen or C1-6alkyl; or R4 and R6 taken together can be xe2x80x94(CH2)qxe2x80x94 when m is 1 and wherein q is 2 or 3;
R8 and R9 are each independently selected from hydrogen or C1-6alkyl; or R8 and R9 taken together with the nitrogen to which they are attached are morpholin4-yl, piperazin-1-yl, piperidin-1-yl or xe2x80x94NHC(xe2x95x90NH)NH2;
R10 is heteroaryl, said heteroaryl selected from the group consisting of imidazolyl, benzoimidazolyl, thienyl, benzothienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrolyl, thiadiazolyl, oxadiazolyl, triazolyl, triazinyl and tetrazolyl, and said heteroaryl optionally substituted with one to three same or different amino, hydroxy, halogen, C1-6alkyl, morpholin-4-yl, piperazin-1-yl, piperadin-1-yl, phenyl, xe2x80x94CO2H or xe2x80x94CO2C1-6alkyl; and
provided R4 is hydrogen or C1-6alkyl and R5 is C1-6 alkyl when m is 0.
A second embodiment of a first aspect of the present invention is a compound of the first embodiment of the first aspect and of the formula Ia 
or a pharmaceutically acceptable salt thereof, wherein:
L is oxygen; R1 is C1-8alkyl; and R2 and R3 are each independently hydrogen or halogen.
A third embodiment of a first aspect of the present invention is a compound of the second embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R1 is methyl; and R2 and R3 are each independently hydrogen or fluoro.
A fourth embodiment of a first aspect of the present invention is compound of the third embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R2 is hydrogen; R3 is fluoro; and L1 is R4xe2x80x94(CH2)mxe2x80x94CR5(NR6R7)C(O)xe2x80x94 or R8R9Nxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94.
A fifth embodiment of a first aspect of the present invention is a compound of the fourth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein:
L1 is R4xe2x80x94(CH2)mxe2x80x94CR5(NR6R7)C(O)xe2x80x94; R4 is selected from the group consisting of hydrogen, hydroxy, thiomethoxy, 1H-imidazol-4-yl, indolyl, xe2x80x94CO2H and xe2x80x94NHC(xe2x95x90NH)NH2; R5 is hydrogen or C1-6alkyl, said C1-6alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl and 2-methyipropyl; or R4 and R5 taken together can be xe2x80x94CH2xe2x80x94 when m is 0; R6 is hydrogen or methyl; or R4 and R6 taken together can be xe2x80x94(CH2)qxe2x80x94 when m is 1 and wherein q is 2 or 3; R7 is hydrogen or C1-6alkyl, said C1-6alkyl selected from the group consisting of methyl, ethyl, propyl and isopropyl.
A sixth embodiment of a first aspect of the present invention is a compound of the fifth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R4 and R6 taken together are xe2x80x94(CH2)q wherein q is 2 or 3; and m is 1.
A seventh embodiment of a first aspect of the present invention is a compound of the fifth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R4 is hydrogen; m is 0;
R5 is C1-6alkyl, said C1-6alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl and 2-methylpropyl; and R6 and R7 are each independently hydrogen or methyl.
An eighth embodiment of a first aspect of the present invention is a compound of the fifth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from the group consisting of hydroxy, thiomethoxy, 1H-imidazol-4-yl, xe2x80x94CO2H and xe2x80x94NHC(xe2x95x90NH)NH2; R5 is hydrogen; R6 and R7 are hydrogen; and m is an integer from 1to 3.
A ninth embodiment of a first aspect of the present invention is a compound of the fourth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: L1 is R8R9Nxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94;
R8 and R9 are each independently selected from hydrogen or C1-6alkyl; said C1-6alkyl selected from the group consisting of methyl, ethyl and propyl; or R8 and R9 taken together with the nitrogen to which they are attached are morpholin-4-yl or xe2x80x94NHC(xe2x95x90NH)NH2; and n is an integer from 1 to 3.
A tenth embodiment of a first aspect of the present invention is a compound of the third embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein:
L1 is C1-6alkylC(O)CH2C(O)xe2x80x94; R2 is hydrogen; and R3 is fluoro.
An eleventh embodiment of a first aspect of the present invention is a compound of the third embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: L1 is R10xe2x80x94Xxe2x80x94CH2C(O)xe2x80x94; X is selected from the group consisting of a bond, sulfur, oxygen and NH; R2 is hydrogen; and R3 is fluoro.
A twelth embodiment of a first aspect of the present invention is a compound of the eleventh embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R10 is heteroaryl, said heteroaryl selected from the group consisting of imidazolyl, benzoimidazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl, tetrazolyl, and triazolyl, and said heteroaryl optionally substituted with one to three same or different amino, hydroxy, C1-6alkyl, phenyl or xe2x80x94CO2C1-6alkyl.
A thirteenth embodiment of a first aspect of the present invention is compound of the third embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: L1 is R10xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94; R2 is hydrogen; and R3 is fluoro.
A fourteenth embodiment of a first aspect of the present invention is a compound of the third embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: L1 is R10xe2x80x94NHC(O)CH2xe2x80x94; R2 is hydrogen; and R3 is fluoro.
A fifteenth embodiment of a first aspect of the present invention is a compound of the fourteenth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R10 is heteroaryl, said heteroaryl selected from the group consisting of triazolyl, thiadiazolyl and imidazolyl, and said heteroaryl optionally substituted with one C1-6alkyl or morpholin-4-yl.
A sixteenth embodiment of a first aspect of the present invention is a compound of the third embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: L1 is R10xe2x80x94(CH2)pxe2x80x94; R2 is hydrogen; and R3 is fluoro.
A seventeenth embodiment of a first aspect of the present invention is a compound of the sixteenth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R10 is pyrol-1-yl or indol-3-yl; and p is 2 or 3.
An eighteenth embodiment of a first aspect of the present invention is a compound of the third embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: L1 is R10xe2x80x94S(O)2xe2x80x94; and R2 is hydrogen.
A nineteenth embodiment of a first aspect of the present invention is a compound of the eighteenth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R10 is heteroaryl, said heteroaryl selected from imidazolyl or isoxazolyl, and said heteroaryl optionally substituted with one or two C1-6alkyl.
A twentieth embodiment of a first aspect of the present invention is a compound of the first embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
N-[4-(4-{4-[2-Amino-3-(1H-indol-3-yl)-propionyl]-piperazin-1-yl}-3-fluoro-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(4-{4-[2-Amino-3-(1H-imidazol-4-yl)-propionyl]-piperazin-1-yl}-3-fluoro-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-(4-{3-Fluoro-4-[4-(3-oxo-butyryl)-piperazin-1-yl]-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-(4-{4-[4-(2-Amino-acetyl)-piperazin-1-yl]-3-fluoro-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-(4-{3-Fluoro-4-[4-(2-1H-imidazol-4-yl-acetyl)-piperazin-1-yl]-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-(4-{3-Fluoro-4-[4-(3-1H-imidazol-4-yl-acryloyl)-piperazin-1-yl]-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-[4-(4-{4-[2-(1H-Benzoimidazol-2-ylsulfanyl)-acetyl]-piperazin-1-yl}-3-fluoro-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(4-methyl-4H-[1, 2, 4]triazol-3-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
2-[2-(4-{4-[2-(Acetylamino-methyl)-5-oxo-2,5-dihydro-isoxazol-4-yl]-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo-ethylsulfanyl)-1H-imidazole-4-carboxylic acid ethyl ester;
2-(4-{4-[2-(Acetylamino-methyl)-5-oxo-2,5-dihydro-isoxazol-4-yl]-2-fluoro-phenyl}-piperazin-1-yl)-N-(1H-imidazol-2-yl)-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(5-phenyl-4H-[1, 2, 4]triazol-3-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(pyrimidin-2-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-(4-{3-Fluoro-4-[4-(2-morpholin-4-yl-acetyl)-piperazin-1-yl]-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(4-{4-[2-(5-Amino-[1,3,4]thiadiazol-2-ylsulfanyl)-acetyl]-piperazin-1-yl}-3-fluoro-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-([1,3,4]thiadiazol-2-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(4H-[1,2,4]triazol-3-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(thiazol-2-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(1-methyl-1H-tetrazol-5-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(1H-imidazol-2-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
2-(4-{4-[2-(Acetylamino-methyl)-5-oxo-2,5-dihydro-isoxazol-4-yl]-2-fluoro-phenyl}-piperazin-1-yl)-N-[1, 3, 4]thiadiazol-2-yl-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(5-hydroxy-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-[4-(3-Fluoro-4-{4-[2-(6-methyl-pyridin-3-yloxy)-acetyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide;
N-(4-{4-[4-(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperazin-1-yl]-3-fluoro-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-(4-{4-[4-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-piperazin-1-yl]-3-fluoro-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-(4-{3-Fluoro-4-[4-(1-methyl-1H-imidazole-4-sulfonyl)-piperazin-1-yl]-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-(4-{4-[4-(1-Methyl-1H-imidazole-4-sulfonyl)-piperazin-1-yl]-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide;
N-(4-{3-Fluoro-4-[4-(3-pyrrol-1-yl-propyl)-piperazin-1-yl]-phenyl}-5-oxo-5H-isoxazol-2-ylmethyl)-acetamide; and
N-[4-(3-Fluoro-4-{4-[2-(1H-indol-3-yl)-ethyl]-piperazin-1-yl}-phenyl)-5-oxo-5H-isoxazol-2-ylmethyl]-acetamide.
A first embodiment of a second aspect of the present invention is a pharmaceutical composition comprising a compound of any of the first through twentieth embodiments of the first aspect in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
A first embodiment of a third aspect of the present invention is a method of treating a bacterial infection in a mammal which comprises administering a therapeutically effective amount of a compound of any of the first through twentieth embodiments of the first aspect to a mammal in need thereof.
The compounds of this invention are structurally distinct from the previously reported oxazolidinone, isoxazoline and isoxazolinone antibiotics. The compounds of formula I are antibacterial agents useful in the treatment of infections in humans and other animals caused by a variety of bacteria, particularly methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. 
Also included in the invention are processes for preparing the compounds of formula I and pharmaceutical compositions containing said compounds in combination with pharmaceutically acceptable carriers or diluents.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein is intended to include the non-toxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like. These salts may be in hydrated form.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro.
The aliphatic xe2x80x9calkylxe2x80x9d groups as used herein means straight or branched chains having the specified number of carbon atoms, e.g. in the case of C1-6 alkyl, the alkyl group may have from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. Similarly, xe2x80x9cthioalkoxyxe2x80x9d refers to a group of the formula xe2x80x94SR where R is an alkyl radical as defined above.
The term xe2x80x9calkoxyxe2x80x9d alone or in combination means an alkyl ether radical where the alkyl portion is as defined above, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated monocyclic hydrocarbon radical having the designated number of carbon ring members, e.g. cyclopropyl, cyclolbutyl, cyclopentyl and cyclohexyl. Similarly, the term xe2x80x9ccycloalkenylxe2x80x9d means an unsaturated monocyclic hydrocarbon radical having the designated number of carbon ring members and at least one double bond.
xe2x80x9cHeteroarylxe2x80x9d as used herein refers to an aromatic heterocyclic moiety having one or more atoms selected from oxygen, nitrogen or sulfur. Such ring systems include, but are not limited to, pyridinyl, thienyl, furanyl, pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyn, 3-quinolyn, 1-isoquinolyl, 3-isoquinolyl, 2-imadazolyl, 4-imadazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiazol-3-yl, 1,2,4-thiazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl.
Some specific preferred embodiments of the present invention are listed in the table below.
The compounds of the present invention can be made by the methods summarized below. It will be apparent to those skilled in the art that the procedures described herein are representative in nature and that alternative procedures are feasible.
The synthesis of amide-linked piperazines of type 35 and 36 is illustrated in Scheme 1. Piperazine trifluoroacetic acid salts of type 32 can be synthesized according to the methods described by Snyder and Zheng International Patent Application WO 00/10566). In situ formation of the free base of 32, and subsequent treatment with bromoacetyl chloride affords intermediates 34. Substitution of the bromine by amines of formula Rxe2x80x2Rxe2x80x3NH (in which Rxe2x80x2Rxe2x80x3NH represents amines such as R8R9NH, R10NH2 or R10NHC1-6alkyl), or, thiols, such as those of general formula R10SH, alcohols of general formula R10OH, or phenols gives products of type 35 and 36. 
An additional method to synthesize piperazine amide derivatives of type 37 from trifluoroacetic acid salts of type 32 is depicted in Scheme 2. The amine salt 32 and a suitable carboxylic acid (in which RCO2H may represent suitable acids such as R4xe2x80x94(CH2)mxe2x80x94CR5(NR6R7)C(O)OH, R8R9Nxe2x80x94(CH2)nxe2x80x94C(O)OH, C1-6alkylC(O)CH2C(O)OH, R1xe2x80x94Xxe2x80x94CH2C(O)OH or R10xe2x80x94CHxe2x95x90CHxe2x80x94C(O)OH) are coupled using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) with conditions well known to those skilled in the art to provide amides 37. 
Amide derivatives of type 40 can be synthesized according to the method of Scheme 3. Amine salt 32 is converted to the free base in situ, and is then alkylated with t-butyl bromoacetate to yield esters 38. Cleavage of the t-butyl ester with trifluoroacetic acid (TFA) provides carboxylic acid intermediate 39. Coupling of 39 with amines, such as R10NH2, or ammonium salts using EDC provides amides 40. 
The free amine 41 can be utilized as starting material for synthesis of new isoxazolinone derivatives as depicted in Scheme 4 and Scheme 5. Coupling of 41 with various carboxylic acids (Scheme 4) using dicyclohexylcarbodiimide (DCC) or acid chlorides (using standard conditions known to those skilled in the art) serves to produce amides of type 37. Treatment of 41 with sulfonyl chlorides leads to sulfonamides 43. The reaction of amine 41 with various aldehydes utilizing reductive amination conditions well known in the art, exemplified by Pae et al. (Bioorg. Med. Chem. Lett. 1999, 9, 2679), leads to alkyl piperazines of type 42. Alkyl piperazines 42 can also be accessed by direct alkylation of amine 41 with substituted alkyl halides or sulfonates 44, many of which are commercially available. Alkyl halides or sulfonates 44 can also be easily synthesized according to the methods of Fries et aL (J. Med. Chem. 1979, 22, 356), Nordlander et al. (Zh. Org. Khim. 1996, 32 (12) 1883) or Geminer et al. (Bioorg. Med. Chem. Lett. 1993, 3 (8), 1477), or by numerous additional methods well known to those skilled in the art. 
An additional method to produce piperazine derivatives of type 37 is illustrated by Scheme 5. Direct acylation of amine 41 with lactones, esters or anhydrides in an appropriate solvent, using conditions well known to those skilled in the art, affords piperazines 37. 
It will be understood that where the substituent groups used in the above reactions contain certain reaction-sensitive functional groups which might result in undesirable side-reactions, such groups may be protected by conventional protecting groups known to those skilled in the art. Suitable protecting groups and methods for their removal are illustrated in Protective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene, and Peter G. M. Wuts (John Wiley and Sons, 1999). It is intended that such protected intermediates and end-products are included within the scope of the present invention and claims.
Some of the desired end-products of formula I contain an amine. In these cases the final product may be isolated as a pharmaceutically acceptable acid addition salt by addition of an appropriate acid such as HCl, HBr, HI, or methanesulonic acid, etc. It is intended that such salts are included within the scope of the present invention and claims.
It will be appreciated that certain products within the scope of formula I may have substituent groups which can result in optical isomers. It is intended that the present invention include within its scope all such optical isomers as well as epimeric mixtures thereof (i.e., R-, S-, or racemic forms).
The compounds of the present invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly humans. The novel compounds of formula I, or pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics active against Gram-positive bacteria. While they may be used in animal feed as additives for the promotion of growth, as preservatives for food, as bactericides in industrial applications, for example in water-based paint and in the white water of paper mills to inhibit the growth of harmful bacteria, and as disinfectants for destroying or inhibiting the growth of harmful bacteria on medical and surgical equipment, they are especially useful in the treatment of bacterial infections in humans and other animals caused by Gram-positive bacteria sensitive to the new derivatives.
The pharmaceutically active compounds of this invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active isoxazolinone ingredient, a pharmaceutically acceptable carrier or diluent. The compound may be administered by a variety of means, for example orally, topically, or parentally (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc., or in liquid form such as solutions, suspensions, or emulsions. Compositions for injection may be prepared in unit dose form in ampules or in multi-dose containers and may contain additives such as suspending, stabilizing, and dispersing agents. The compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
Thus, according to another aspect of the invention, there is provided a method of treating a bacterial infection which comprises administering a therapeutically effective amount of the compound to a host, particularly a mammalian host, and most particularly a human patient. The use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of bacterial infections are also provided.
The dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parentally or orally to mammalian hosts in an amount of from 25 mg/day to 2 g/day.
Samples of the compounds prepared below in Examples 1-6 after solution in water and nutrient broth were found to exhibit the following ranges of Minimum Inhibitory Concentrations (MICs) versus the indicated microorganisms as determined by tube dilution. The MICs were determined using a broth micro dilution assay in accordance with that recommended by the National Committee for Clinical Laboratory Standards (NCCLS). Mueller-Hinton medium was used except for Staphylococci which was treated in Todd Hewitt broth. The final bacterial inoculate contained approximately 5xc3x97105 cfu/mL and the plates were incubated for 18 hours at 35xc2x0 C. in ambient air (Streptococci in 5% CO2). The MIC was defined as the lowest drug concentration that prevented visible growth.